| 학회 | 한국고분자학회 |
| 학술대회 | 2004년 가을 (10/08 ~ 10/09, 경북대학교) |
| 권호 | 29권 2호, p.686 |
| 발표분야 | 의료용 고분자 부문위원회 |
| 제목 | Computation of interaction energy between β-secretase and its enzymatic inhibitors |
| 초록 | β-Secretase is a membrane-associated aspartic protease involved in the production of amyloid peptide in Alzheimer’s disease and is a major target for drug design. Recently, Tang and co-workers have determined the crystal structures of β-secretase complexed with designed inhibitors, OM99-2 and OM00-3.1-5 Although they provided reasonable explanations for the binding affinity of substrate binding sites, the residue preference for the binding sites is not clearly understood yet. In this work, we have generated a number of inhibitors based on the crystal structure of OM00-3 by varying the sequence of OM00-3 and calculated binding energies of inhibitors with β-secretase using the CHARMM program in order to classify the origin of binding affinity of inhibitors to the β-secretase. The site-specific preference of inhibitor for β-secretase is analyzed in terms of van der Waals and electrostatic energies, which shows that the binding affinity is not increased by just hydrophobic or hydrophilic substitution in inhibitors. It is realized that in addition to hydrophobic or hydrophilic interactions the geometry requirements such as the capability of hydrogen bonding and the size of side chain have to be met for the enhancement of binding affinity. Fig. 1. Interaction energy between β-secretase and amino acid in OM00-3 Reference 1. L. Hong, G. Koelsch , X. Lin, S. Wu, S. Terzyan, A. K. Ghosh , X. C. Zhang , J. Tang, Science, 290, 150 (2000). 2. A. K. Ghosh, D. Shin, D. Downs, G. Koelsch, X. Lin, J. Ermolieff, and J Tang, J. Am. Chem. Soc., 122, 3522 (2000). 3. A. K. Ghosh, G. Bilcer, C. Harwood, R. Kawahama, D. Shin, K. A. Hussain, L. Hong, J.A.Loy, C. Nguyen, G. Koelsch, J. Ermolieff, and J. Tang, J. Med. Chem., 44, 2865 (2001). 4. R. T. Turner III , G. Koelsch, L. Hong, P. Castanheira, A. Ghosh, and J. Tang, Biochemistry, 40, 10001 (2001). 5. L. Hong, R. T. Turner III, G. Koelsch, D. Shin, A. K. Ghosh, and J. Tang, Biochemistry, 41, 10963 (2002). |
| 저자 | 최진, 최호섭, 허준, 조원호 |
| 소속 | 서울대 |
| 키워드 | Interaction energy; Inhibitor; Beta-Secretase; OM00-3; Alzheimer's Disease |
